Coronary heart disease (CHD), the leading cause of morbidity and mortality worldwide, is caused by atherosclerotic plaque deposition in the coronary arteries (i.e. atherosclerosis). CHD is a multi-factorial disease, and independent risk factors include: age, gender, hypertension, smoking, diabetes, family history of premature CHD, elevated levels of low density lipoprotein cholesterol (LDL-C) (>160 mg/dl), and decreased levels of high density lipoprotein cholesterol (HDL-C) (<40 mg/dl for males and <50 mg/dl for females). However, these established CHD-risk factors account for only about half of the variability in CHD events in the U.S. population. Accumulating data indicate that emerging risk factors, including lipoprotein sub-fractions, are better markers of CHD than many of the established CHD risk factors. Additionally, other factors such as the genetic background of an individual may influence how much the major risk factors affect absolute risk.
A simple paradigm of atherosclerosis is that there is an antagonistic relationship between apolipoprotein-B (apo-B)-containing particles, such as low density lipoprotein (LDL) particles, and apoA-I-containing particles, such as high density lipoprotein (HDL) particles. For example, apo-B-containing particles promote atherosclerosis (i.e. they are atherogenic) because they are deposited on the arterial wall; however, apoA-I-containing particles counteract this effect (i.e. they are atheroprotective) because they remove excess cholesterol from the arterial wall.
The various HDL subpopulations differ in size and composition, which impart each of the varying HDL subpopulations with different functions and pathophysiological relevance. The many different functions of HDL are not distributed evenly among the various HDL subpopulations. The best illustration of this is the fact that cells have several different ways by which to remove excess cholesterol. Different HDL particles interact with the different pathways specifically depending on the cell type, the expressed receptor protein type on the surface of the cell, and the cellular cholesterol content. Moreover, the different HDL subpopulations participate differently in the anti-oxidation, anti-inflammation, and cell-signaling processes based on the particles' lipid and protein composition.
Most importantly, the HDL subpopulation profile can differentiate subjects with increased risk for CVD from subjects without such risk independently of HDL-C level. This is very important, as some subjects (or even an entire ethnic group) may have low HDL-C levels but present no history of elevated CVD risk. This is due to the fact that these subjects may have not only hyperactive HDL catabolism, but also hyperactive HDL function. However, some subjects with high HDL-C may experience a CVD event due to low HDL metabolism/catabolism or dysfunctional HDL.
Statins have emerged as an important class of therapeutic compounds for the treatment of CHD. Statins are drugs that inhibit HMG CoA reductase, the rate limiting enzyme in cholesterol biosynthesis, and thereby lower LDL cholesterol. By lowering cellular cholesterol synthesis, statins up-regulate the LDL receptor on the liver cell surface, resulting in enhanced LDL apolipoprotein B clearance. Lowering LDL cholesterol with statin therapy reduces the risk of CHD morbidity and mortality. It has been documented that the absolute reduction in statin induced LDL cholesterol lowering clearly predicts reduction in CHD events. Moreover the absolute reduction in LDL cholesterol levels is greatest in subjects with elevated LDL cholesterol levels at baseline. Additionally, lathosterol is a direct precursor of cholesterol in the bloodstream, and serves as an excellent marker of cholesterol biosynthesis. Individuals with elevated plasma lathosterol/cholesterol ratios generally have significantly greater LDL cholesterol lowering in response to statin therapy than individuals with low plasma lathosterol/cholesterol ratios.
The SLCO1B1 gene encodes a liver-specific polypeptide member of the organic anion transporter family. The SLCO1B1 transporter is primarily responsible for the ability of statins to inhibit cholesterol synthesis. About 20% of the population is heterozygous for the rs4149056 allele, while about 3% is homozygous for the rs4149056 allele. The rs4149056 allele (625T>C)) results in an amino acid substitution (V174A) in the SLCO1B1 protein that decreases the function of this transporter, thereby decreasing the efficacy of statin treatment in terms of LDL cholesterol lowering (Niemi M et al. (2006) “SLCO1B 1 polymorphism and sex effect the pharmacokinetics of pravastatin but not fluvastatin.” Clin Pharmacol Ther 80:356-66).
Niemi et al. (2006) reported that following a single oral dose of 40 mg of pravastatin in 32 subjects the areas under the curve of pravastatin blood levels were significantly greater for those subjects carrying the uncommon CC phenotype versus the wildtype TT SLCO1B1 genotype. In a study of 28 subjects, the SLCO1B1 haplotype significantly affected the degree of lathosterol (a marker of cholesterol synthesis) lowering induced by pravastatin (Gerloff T et al. (2006) “Influence of the SLCO1B1*1b and *5 haplotypes on pravastatin's cholesterol lowering capabilities and basal sterol serum levels.” Naunyn Smiedebergs Arch Pharmacol 373:45-50). In another study of 16 healthy volunteers, Igel and colleagues reported that SLCO1B1 haplotype was associated with a doubling of plasma pravastatin levels as compared to other haplotypes (Igel M et al. (2006) “Impact of the SLCO1B1 polymorphism on the pharmacokinetics and lipid-lowering efficacy of multiple-dose pravastatin.” Clin Pharmacol Ther 79:419-26). In addition, it was also found that the SLCO1B1 genotype affected pravastatin metabolism and LDL-C lowering response in 20 children with familial hypercholesterolemia and 12 cardiac transplant recipients (Hedman M et al. (2006) “Pharmacokinetics and response to pravastatin in pediatric patients with familial hypercholesterolemia and in pediatric cardiac transplant recipients in relation to polymorphisms of the SLCO1B1 and ABCB1 genes”. Br J Clin Pharmacol 61:706-15).
The Apolipoprotein E (ApoE) genotype predicts LDL cholesterol lowering response to statins, including atorvastatin and pravastatin. The ApoE gene makes a protein that becomes a lipoprotein when combined with fat. The lipoprotein ApoE is a very low-density lipoprotein, which is responsible in part for removing cholesterol from the bloodstream. Genetic variations in ApoE affect cholesterol metabolism, and may alter an individual's chances of having heart disease, and in particular a heart attack or a stroke.
There are three relatively common variants of ApoE, known as ApoE2, ApoE3, and ApoE4. About 15% of the population carry the ApoE2 allele and are more responsive to statins in terms of LDL cholesterol lowering, while about 20% of the population carry the ApoE4 allele and are less responsive in terms of statin induced LDL cholesterol lowering.
Combinatorial analysis of an individual's genotype at multiple loci and their blood chemistry profile can be used to assess treatment and/or prophylaxis of the individual with respect to coronary heart disease (CHD).